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Coverage-guided fuzzing, is a test technique, where the interfaces of a Program under Test (PUT) are fed with semi-random inputs, mutated to maximize the PUT’s coverage depending on dynamically collected feedback. When measuring tests, there is \(\textit {test effectiveness}\) and \(\textit {test efficiency}\). Test effectiveness can be measured in the number of bugs found during testing. Fuzzing has already been shown to be an effective method to detect bugs. Test efficiency, on the other hand, can be measured with the used resources to get a certain test effect. Achieving complete coverage during testing, in a simple case line coverage, is an immense amount of test creation effort, when only unit tests are used - and most of those unit tests do not add to a thorough overall test. Due to continuously growing software systems, a \(\textit {reasonable effort}\) should be put into creating manual unit test cases. In this paper we propose a combination of unit tests and fuzz tests to reduce the overall effort in test creation. While unit tests are indispensable for functional testing, fuzz tests shine to unveil unwanted non-functional behavior, i.e. generating unexpected edge cases. This results in an overall reduction in manual effort for test creation, while the test effectiveness remains equal, i.e. coverage. We introduce an effort estimation framework for a combined unit test and fuzz test strategy. Additionally, we conduct an empirical case study of multiple automotive network components indicating test creation effort savings of around 26%, when manual (non-functional) unit tests are partly automated with fuzz tests - all while fuzzing discovered the same bugs as tortuous unit tests.

The advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled >25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery, and storage were each harmonized. A compliant and secure network enabled ongoing review and reconciliation of clinical interpretations, while maintaining communication and data sharing between clinicians and investigators. A total of 202 individuals had positive diagnostic findings relevant to the indication for testing and 1,294 had additional/secondary findings of medical significance deemed to be returnable, establishing data return rates for other testing endeavors. This study accomplished integration of structured genomic results into multiple electronic health record (EHR) systems, setting the stage for clinical decision support to enable genomic medicine. Further, the established processes enable different sequencing sites to harmonize technical and interpretive aspects of sequencing tests, a critical achievement toward global standardization of genomic testing. The eMERGE protocols and tools are available for widespread dissemination.

Eine neue Ära an Rechnern ist im Aufbruch - das Internet der Dinge (IoT). Schon heute besteht es aus Milliarden vernetzten Geräten. Wird dieser Trend weitergeführt, dann bietet das IoT großes Geschäftspotential. Deswegen sollten IoT Geräte gegen Angriffe gesichert sein und ein signifikanter Anteil dieser Geräte sollte leichtgewichtige und adäquate Sicherheitsmaßnahmen haben. Aber starke Sicherheit und Kosten stehen nicht im Einklang. Mit dem Einbinden intrinsischer Zufälligkeit von Geräten und Kommunikationen, wird die Fehleranfälligkeit von Systemen verbessert und die Sicherheitsgarantien erhöht bei einem geringen Aufwand. Innerhalb dieser Arbeit zeigen wir, dass physikalisch basierte Sicherheit wohlgeeignet für speicherbeschränkte Geräte ist. Dazu benutzen wir bevorzugt die Primitive Channel-based Key Agreement und Physical Unclonable Function. Kurzgesagt verschieben wir digitale Herausforderungen, wie Schlüsselspeicherung und Schlüsselgenerierung, in die physikalische Domäne.

Background— The American Heart Association (AHA) has defined the concept of ideal cardiovascular health in promotion of the 2020 Strategic Impact Goals. We examined whether adherence to ideal levels of the 7 AHA cardiovascular health metrics was associated with incident cancers in the Atherosclerosis Risk In Communities (ARIC) study over 17 to 19 years of follow-up. Methods and Results— After exclusions for missing data and prevalent cancer, 13 253 ARIC participants were included for analysis. Baseline measurements were used to classify participants according to 7 AHA cardiovascular health metrics. Combined cancer incidence (excluding nonmelanoma skin cancers) from 1987 to 2006 was captured using cancer registries and hospital surveillance; 2880 incident cancer cases occurred over follow-up. Cox regression was used to calculate hazard ratios for incident cancer. There was a significant ( P trend P trend =0.03). Conclusions— Adherence to the 7 ideal health metrics defined in the AHA 2020 goals is associated with lower cancer incidence. The AHA should continue to pursue partnerships with cancer advocacy groups to achieve reductions in chronic disease prevalence.

This review attempts to provide an update on recent research on inherited susceptibility to ovarian cancer. It covers articles mainly published in 2002 and 2003, with an emphasis on genetic counseling issues.The major areas on which recent reports have focused include: (1) an expanded understanding of the BRCA1 and BRCA2 mutation spectrum and the frequencies of deleterious alleles in various ethnic groups; (2) investigations on how information is best transmitted to high-risk family members via genetic counseling; (3) an analysis of patient management changes based on genotype results; (4) social issues surrounding predictive testing for breast/ovarian cancer genes, including health insurance and discrimination concerns; and (5) an investigation into gynecologists' knowledge of ovarian cancer genetics, and their ability to provide genetic counseling for ovarian cancer to their patients. Preliminary reports from scientific meetings that have not yet been published in peer-reviewed journals are also discussed.Recent developments in ovarian cancer genetics expand many of the areas that have been studied previously. A major focus of recent research has dealt with genetic counseling for families affected by hereditary breast and ovarian cancer.

A proportion of cases of breast and colon cancers are caused by inherited mutations that confer a greatly increased susceptibility to malignancy. Certain clinical features may help distinguish patients with a genetic cause for their cancer from the larger number of patients with sporadic tumors. A thorough family medical history is also necessary to identify those at high risk for developing cancer. Many of the normal functions of these genes are understood, and mutation analysis for patients and their families is now available as a clinical service. Presymptomatic detection of mutations allows the patient to pursue preventive measures to reduce the probability of developing a malignancy. Evidence is now available that some prophylactic measures do reduce the incidence of cancer and reduce mortality in mutation carriers, and the standard of care is evolving rapidly. The essential elements necessary to provide accurate interpretations of molecular genetics test results to patients are described.

Background Low serum magnesium levels have been associated with multiple chronic diseases. The regulation of serum magnesium homeostasis is not well understood. A previous genome-wide association study (GWAS) of European ancestry (EA) populations identified nine loci for serum magnesium. No such study has been conducted in African-Americans, nor has there been an evaluation of the interaction of magnesium-associated SNPs with environmental factors. The goals of this study were to identify genetic loci associated with serum magnesium in an African-American (AA) population using both genome-wide and candidate region interrogation approaches and to evaluate gene-environment interaction for the magnesium-associated variants in both EA and AA populations. We conducted a GWAS of serum magnesium in 2737 AA participants of the Atherosclerosis Risk in Communities (ARIC) Study and interrogated the regions of the nine published candidate loci in these results. Literature search identified the influence of progesterone on MUC1 expression and insulin on TRPM6 expression. Results The GWAS approach in African-American participants identified a locus near MUC1 as genome-wide significant (rs2974937, beta = −0.013, p = 6.1x10−9). The candidate region interrogation approach identified two of the nine loci previously discovered in EA populations as containing SNPs that were significantly associated in African-American participants (SHROOM3 and TRPM6). The index variants at these three loci together explained 2.8 % of the variance in serum magnesium concentration in ARIC African-American participants. On the test of gene-environment interaction in ARIC EA participants, the index variant at MUC1 had 2.5 times stronger association in postmenopausal women with progestin use (beta = −0.028, p = 7.3x10−5) than in those without any hormone use (beta = −0.011, p = 7.0x10−8, p for interaction 0.03). At TRPM6, the index variant had 1.6 times stronger association in those with lower fasting insulin levels (

A 25-year-old woman with maple syrup urine disease (MSUD) developed generalized weakness over 1 week. She had severe leg and moderate arm weakness, areflexia, and distal sensory loss. Plasma branched-chain amino acid concentrations were elevated, reflecting an acute exacerbation of the disease. Electrodiagnostic studies indicated an acute axonal polyneuropathy and sural nerve biopsy revealed acute wallerian degeneration without inflammation. Peripheral neuropathy, although not identified previously as a clinical feature of MSUD, may become more common as chronic dietary restrictions and improved management of the disease allow survival into adulthood.

Pheochromocytoma and paraganglioma (PGL) are extremelyrare neuroendocrine tumors in children. The WHO classificationconsiders pheochromocytoma to arise from the adrenal medullawhile PGL are tumors arising from the sympathetic or para-sympathetic autonomic ganglia outside the adrenal gland (extra-adrenalpheochromocytoma)[1].PheochromocytomaandPGLmaybe either syndrome-related or sporadic. Syndromes that may occurwithpheochromocytomaincludemultipleendocrineneoplasiatype2 (MEN2), von Hippel-Lindau (VHL) disease and rarely neuro-fibromatosis type 1 (NF1), and are associated with germlinemutationsoftheRET,VHL,andNFgenes,respectively.Inaddition,familial PGL syndromes characterized by a positive family historyof paraganglioma are associated with germline mutations in thegenes that encode the B, C, and D subunits of the mitochondrialcomplex II enzyme succinate dehydrogenase (SDHB, SDHC, andSDHDgenes)[2,3].IthasbeenshownthatevenapparentlysporadiccasesofPGLarestronglyassociatedwithgermlinemutationsintheSDHgene[4].Furthermore,patientswithmalignantPGLfrequentlyharborgermlinemutationsintheSDHBgene[5].MalignantPGLisfrequent in children with a PGL diameter >6cm and apparentlysporadic disease [6]. Here we describe a child who presented withdiffusely metastatic PGL with compound heterozygous mutationleading toanovel splice donorregionDNAsequencevariant intheSDHB gene.

Von Hippel-Lindau (VHL) syndrome (OMIM 193300) is an autosomal dominant disorder caused by deletions or mutations in a tumor suppressor gene mapped to human chromosome 3p25. It is characterized clinically by vascular tumors, including retinal and central nervous system hemangioblastomas (cerebellar, spinal, and brain stem). Hemangioblastomas are benign and do not metastasize. Other features include cysts of the kidneys, liver, and pancreas. Clear cell renal cell carcinoma occurs in up to 70% of patients with VHL and is a frequent cause of death. Pheochromocytomas occur in association with specific alleles of the VHL gene; therefore, a family history of pheochromocytoma in association with VHL is an indication for thorough surveillance for pheochromocytoma in affected family members. Recently, it has been appreciated that patients with VHL may develop endolymphatic sac tumors, which can cause tinnitus or deafness. The diagnosis of VHL may be made in a patient with a family history of VHL based on a single retinal or cerebellar hemangioblastoma, renal cell carcinoma or pheochromocytoma, and, possibly, multiple pancreatic cysts. Renal and epididymal cysts are not sufficient to make the diagnosis of VHL. In the absence of a family history of VHL the presence of two or more retinal or cerebellar hemangioblastomas, or one hemangioblastoma with one visceral tumor, is required for diagnosis. Studies of the natural history of VHL showed a life expectancy less than 50 years before surveillance protocols were developed. Annual assessments (physical and ophthalmologic examinations) should begin in infancy. Imaging of abdominal organs and the brain and spine should be added in teenagers and adults. Renal cysts and tumors should be monitored by computed tomography every 6 months. Mutation analysis has allowed presymptomatic identification of affected family members; those found not to have inherited the gene do not need to be monitored. The VHL gene coding sequence contains three exons, and two isoforms of mRNA exist, reflecting the presence or absence of exon 2. Tumors arise after the loss or inactivation of the wild type allele in a cell. About 20% of patients have large germline mutations detectable by Southern blot analysis, 27% have missense mutations, and 27% have nonsense or frameshift mutations. In about 20% of VHL families no deletion or mutation can be detected. Families may be characterized by the presence (type 2; 7% to 20% of families) or absence (type 1) of pheochromocytomas. Most type 2 families have missense mutations, whereas most type 1 families are affected by deletions or premature termination mutations. Prognostic counseling regarding the lifetime risk of pheochromocytoma can be aided by determination of the underlying mutation in patients without family histories of VHL.

Although most cases of ovarian cancer occur sporadically, some families carry germline mutations that can increase the risk for developing ovarian and other cancers substantially. Practitioners need to recognize characteristics of an individual patient or family to identify those who are more likely to carry one of these mutations and who might benefit from genetic testing. There is not a known gene that increases the risk only for ovarian cancer. Mutations in two well-established genes, BRCA1 and BRCA2, increase the risk substantially for both breast cancer and ovarian cancer. Mutations in other more recently discovered and less common cancer susceptibility syndrome genes increase the risk for ovarian cancer, along with increasing the risk for several other cancers specific to each syndrome. A thorough family medical history can identify relatives whose medical history may be related to the current patient’s situation. It is also necessary to understand the strategies to follow in identifying which family member is most informative for initial testing, how to interpret the test results, and what to recommend regarding testing for relatives. For patients at increased risk of developing ovarian cancer due to germline mutations, guidelines have been published with the goal of reducing morbidity and mortality among those at highest risk.

We report a 64-year-old man with arthritis and nodules to describe that this picture can be caused by normo-lipidemic xanthomas. Light and electron microscopy (EM) plus polymerase chain reaction (PCR) studies were performed for diagnosis and investigation. These showed features typical of xanthomas plus PCR and EM evidence of possible infection with Chlamydia pneumoniae as a pathogenetic mechanism deserving consideration. With such rare diseases, any clues to possible mechanisms seem important to record and thus to encourage future investigations. This uncommon cause of arthritis and nodules had been confused with rheumatoid arthritis by others in this case.

Pheochromocytoma and paraganglioma (PGL) are rare neuroendocrine tumors in children. Apparently sporadic cases of PGL may harbor germline mutations in the succinate dehydrogenase (SDHx) gene. SDHB mutations are associated with malignant disease. We report a 13-year-old African American boy with diffusely metastatic PGL and compound heterozygous mutation leading to a novel splice donor region DNA sequence variant in the SDHB gene. Family history was positive for non-classical congenital adrenal hyperplasia and pituitary adenoma. After surgical resection of the primary PGL and chemotherapy, he was treated with metaiodobenzy lguanidine (MIBG) combined with arsenic trioxide. At 3-year follow-up, he had stable disease.

Background Interstitial deletions of 3q29 have been recently described as a microdeletion syndrome mediated by nonallelic homologous recombination between low-copy repeats resulting in an ~1.6 Mb common-sized deletion. Given the molecular mechanism causing the deletion, the reciprocal duplication is anticipated to occur with equal frequency, although only one family with this duplication has been reported. Results In this study we describe 14 individuals with microdeletions of 3q29, including one family with a mildly affected mother and two affected children, identified among 14,698 individuals with idiopathic mental retardation who were analyzed by array CGH. Eleven individuals had typical 1.6-Mb deletions. Three individuals had deletions that flank, span, or partially overlap the commonly deleted region. Although the clinical presentations of individuals with typical-sized deletions varied, several features were present in multiple individuals, including mental retardation and microcephaly. We also identified 19 individuals with duplications of 3q29, five of which appear to be the reciprocal duplication product of the 3q29 microdeletion and 14 of which flank, span, or partially overlap the common deletion region. The clinical features of individuals with microduplications of 3q29 also varied with few common features. De novo and inherited abnormalities were found in both the microdeletion and microduplication cohorts illustrating the need for parental samples to fully characterize these abnormalities. Conclusion Our report demonstrates that array CGH is especially suited to identify chromosome abnormalities with unclear or variable presentations.

It has been suggested that inherited traits play a role in the development of osteoporosis by providing a background for the modulation of gene expression. In this study, we examine the influence of the different alleles of alpha 2-HS glycoprotein (AHSG), a protein of the bone matrix, on quantitative estrogens, estrone and estradiol, and bone measures, bone area and density. Estrogens provide a protective effect against fractures in older women and were thus included in the analyses. Isoelectric focusing of AHSG from sera followed by immunoblotting was used to type 163 white postmenopausal women participating in a clinical trial of the effects of walking on bone loss. Plasma hormones were measured by a combination of extraction, column chromatography, and radioimmunoassay; bone measures on the dominant radius were determined with computerized tomography. Analysis of variance was done on estrogen and bone measures after controlling for the effects of age and body mass index. The two major alleles of AHSG result in three phenotypes, designated AHSG 1-1, AHSG 2-1, and AHSG 2-2. The AHSG 1-1 homozygote showed a decreased concentration of estradiol, the AHSG 2-2 homozygote showed an increased concentration, and the AHSG 2-1 heterozygote was intermediate (P = 0.001). Estrone demonstrated a similar pattern in residual analysis although it did not reach statistical significance.

Titelblatt und Inhaltsverzeichnis Abkürzungsverzeichnis Einleitung Material und Methoden Ergebnisse Diskussion Zusammenfassung / Summary Literaturverzeichnis Danksagungen, Lebenslauf, AKAP-Ht31/AKAP-Lbc gehört zu der Familie der A kinase anchoring proteins. Es weist eine ubiquitäre Verbreitung auf und ist in seiner Interaktion mit verschiedenen anderen physiologisch relevanten Proteinen in zahlreiche regulatorische Zellprozesse eingebunden. In der vorliegenden Arbeit wurden zunächst anti-AKAP-Ht31-Antikörper in Kreuz- Immunpräzipitationsstudien mit MCF-7-Zellen getestet, um ihre Spezifität gegen AKAP-Ht31-Spleißvarianten zu charakterisieren. Insgesamt konnten im Western Blot nach Immunpräzipitation bis zu neun mögliche AKAP-Ht31-Spleißvarianten mit Molekulargewichten von 70 kDa bis >250 kDa detektiert werden. Im weiteren Verlauf dieser Arbeit wurden AKAP-Proteine der Größen 40 kDa, 60 kDa, 80 kDa und 160 kDa in MCF-7-Zellen mittels einer cAMP-Agarose- Präzipitation angereichert und anhand des RII-overlays detektiert. Der nukleare Steroid/Thyroid-Rezeptor ERα wurde ebenfalls nach cAMP-Agarose- Präzipitation im Western Blot detektiert. Dies spricht für das Vorhandensein eines Komplexes aus einem funktionellen AKAP-Protein, daran gebundenen ERα und, über die RII-Bindungsdomäne des AKAP-Protein verankerter, PKA. Die Identifizierung potentiell beteiligter AKAP-Ht31-Spleißvarianten nach Immunpräzipitation im RII-overlay führte zu vier Proteinen. Zwei Proteine mit einem Molekulargewicht >220 kDa, von denen das größere wahrscheinlich das gesamte AKAP-Ht31/AKAP-Lbc (309 kDa) und das kleinere eine weitere AKAP- Ht31-Spleißvariante oder ein proteolytisches Abbauprodukt darstellt. Des Weiteren kommt die AKAP-Ht31-Spleißvariante Brx und eine 80-kDa-Protein als Interaktionspartner von ERα in Frage. In Immunfluoreszenzstudien in MCF-7-Zellen konnte gezeigt werden, dass zumindest eine AKAP-Ht31-Variante in unbehandelten Zellen mit ERα kolokalisiert und nach E2-Behandlung mit dem Rezeptor in den Nukleus transloziert. Die Ergebnisse deuten darauf hin, dass das vollständige AKAP-Ht31/AKAP-Lbc und/oder eine kleinere Variante mögliche Interaktionspartner von ERα sind. Um AKAP-Ht31 vollständig zu erhalten (ein 4,5-kb-Fragment des 3 -Endes existierte bereits), wurde das 5 -Ende seiner Nukleotidsequenz aus einer humanen Nieren-cDNA-Expressionsbibliothek (Stratagene, Heidelberg) kloniert. Aus dem vollständigen wildtypischen Klon von AKAP-Ht31/AKAP-Lbc wurden die klassische Bindedomäne der PKA-RII-Untereinheiten (Ht-RII), die nicht- kanonische (zweite) Bindedomäne der PKA-RII-Untereinheiten (Ht-2.RII) und die Pleckstrin-homology und Dbl-homology (DHPH-) Domäne als GFP-Konstrukte kloniert., AKAP-Ht31/AKAP-Lbc belongs to the family of the A kinase anchoring proteins. This AKAP shows an ubiquitous distribution, interacts with many different physiological relevant proteins and is involved in a number of regulatory processes within the cell. Anti-AKAP-Ht31/AKAP-Lbc-antibodies were tested in cross-immunoprecipitation studies in MCF-7 cells, to characterize their specifity against AKAP-Ht31 /AKAP-Lbc splice variants. Using the Western Blot technique after immunoprecipitation, up to nine potential AKAP-Ht31/AKAP-Lbc splice variants with molecular weight ranging from 70 kDa till >250 kDa were detected. In the next part of this work, AKAPs with molecular weight of 40 kDa, 60 kDa, 80 kDa and 160 kDa were enriched in MCF-7 cells using cAMP-agarose- precipitation and subsequently detection with RII-overlay assays. Additionally the nuclear steroid/thyroid receptor ERα had been detected in Western Blot assays after cAMP-agarose-precipitation. This was the first hint for a complex consisting of ERα, PKA and an AKAP. Four potential involved AKAP-Ht31 splice variants were then identified using again the RII-overlay technique after immunoprecipitation. Two proteins with molecular weight >220 kDa. The bigger protein most likely represents full- length, 309 kDa AKAP-Ht31. The smaller protein might be a new AKAP-Ht31 splice variant or a proteolytic degradation product. The AKAP-Ht31 splice variant Brx and a 80 kDa protein are also candidates for the interaction with ERα. Immunofluorescence studies in MCF-7 cells showed, that at least one AKAP-Ht31 splice variant co-localizes in untreated cells with ERα and co-transports with the receptor after E2-treatment into the nucleus. These findings point to the possibility that full-length AKAP-Ht31 and/or a smaller splice variant might interact with ERα. In order to gain the full-length AKAP-Ht31/AKAP-Lbc the 5 -end was cloned using a human kidney cDNA expression library (Stratagene, Heidelberg). In the next part of this work, a full-length AKAP-Ht31/AKAP-Lbc construct was used to clone the classical binding domain of PKA-RII-subunits (Ht-RII), the potential second binding domain of PKA-RII-subunits (Ht-2.RII) and the Pleckstrin- and Dbl-homology (DHPH-) Domain into GFP-vectors.

Coronary heart disease (CHD) remains the leading cause of death in the United States. It is now well established that cholesterol is an important, reversible risk factor for CHD. This article provides a brief background on classification of the dyslipidemias, then discusses current recommendations for the evaluation and treatment of hyperlipidemia. Other risk factors currently being investigated as they relate to the development of CHD are discussed.

We describe a second family with mother to son transmission of omodysplasia, a rare skeletal dysplasia characterized by shortened humeri, shortened first metacarpals and craniofacial dysmorphism. The mother in this family had been diagnosed previously with Robinow syndrome; subsequently, her diagnosis was reclassified. Her pregnancy was closely monitored antenatally with serial ultrasound examinations. Delayed ossification of the humerus was noted prenatally. Her son had ambiguous genitalia and similar skeletal manifestations as his mother. A comparison to other known and suspected cases of dominant omodysplasia is presented. Our observations confirm the existence of a dominant variant of omodysplasia, document genital hypoplasia as an important feature of this syndrome in males and highlight the need to differentiate this entity from Robinow syndrome.

The von Hippel-Lindau (VHL) syndrome (OMIM 193300) is an autosomal dominant disorder caused by deletions or mutations in a tumor suppressor gene on human chromosome 3p25. It is characterized clinically by vascular tumors including benign hemangioblastomas of the cerebellum, spine, brain stem and retina. Clear-cell renal cell carcinoma is a frequent cause of death, occurring in up to 70% of patients with VHL. Pheochromocytomas occur in association with specific alleles (usually mutations as opposed to deletions), therefore a family history of pheochromocytoma in association with VHL is an indication for thorough surveillance for pheochromocytoma in affected family members. The VHL gene coding sequence contains three exons. Two isoforms of mRNA exist, reflecting the presence or absence of exon 2. Tumors arise following the loss or inactivation of the wild-type allele in a cell. In initial studies approximately 20% of patients had large germline mutations detectable by Southern blot analysis, 27% had missense mutations and 27% had nonsense or frameshift mutations. Advances in mutation analysis now allow for a 100% mutation detection rate in families with definite VHL. Families may be characterized by the presence [type 2 (7-20% of families)] or absence (type 1) of pheochromocytomas. Most type 2 families are affected by missense mutations, whereas most type 1 families have deletions or premature termination mutations. The prognosis for the lifetime risk of pheochromocytoma can be estimated by determination of the underlying mutation even if there is no family history of VHL.

Niaspan, when added to a stable dose of a statin in 66 subjects, was found to be safe and highly effective in improving lipid parameters. Subgroup analyses demonstrated its effectiveness in lowering low-density lipoprotein cholesterol in persons not at the National Cholesterol and Education Program low-density lipoprotein cholesterol target and in raising high-density lipoprotein cholesterol in persons with levels < 40 mg/dl.

Patients with rheumatologic diseases often have adverse lipid profiles, either because of the nature of the underlying disease or the side effects of medication. This may place them at increased risk for atherosclerotic cardiovascular diseases, such as coronary artery disease, cerebral vascular disease, and peripheral vascular disease. Patients with rheumatologic diseases should be screened for dyslipidemia. Treatment begins with modifications of diet and lifestyle but often lipid-lowering medications are required to reduce the risk of atherosclerosis. The selection of lipid-lowering agents depends on the lipid profile, side effects, concurrent medications, and patient acceptability. Lipoprotein disorders are important and common risk factors for atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease, cerebrovascular disease, and peripheral vascular disease. 15 Clinical trials have definitively established that reduction of plasma cholesterol significantly reduces the risk of cardiovascular events, revascularization procedures, and total mortality in patients with and without established ASCVD. 16 Lipoprotein metabolism is often influenced by rheumatologic conditions or by medications used to treat these disorders and, therefore, many of these patients have hypercholesterolemia or other associated lipoprotein abnormalities. Furthermore, many rheumatologic conditions are associated with an increased risk of premature ASCVD. The identification and appropriate treatment of lipoprotein disorders in rheumatology patients thus has substantial implications for reducing the burden of ASCVD in this population. Lipoproteins are large, macromolecular complexes that transport cholesterol and triglycerides within the blood. 40 The five major families of lipoproteins are chylomicrons, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL), and high density lipoproteins (HDL). Chylomicrons are the largest and most lipid-rich lipoproteins, whereas HDL are the smallest lipoproteins and contain the least amount of lipid. The major metabolic pathways of lipoproteins are shown in Figures 1–3 and described in the accompanying legends. Apolipoproteins are the major protein components of lipoproteins; they are required for the structural integrity of lipoproteins and direct their metabolic interactions with enzymes, lipid transport proteins, and cell surface receptors. Quantifying certain apolipoproteins may be useful in the diagnosis of some lipid disorders and in the assessment of cardiovascular risk. 42 Lipoprotein receptors mediate cellular interactions with lipoproteins. The best understood lipoprotein receptor is the LDL receptor, which is responsible for catabolizing chylomicron and VLDL remnants and LDL, and is defective in the inherited disorder familial hypercholesterolemia. 3 Finally, lipid-modifying enzymes and lipid transport proteins play a major role in lipoprotein metabolism. One focus of this article is to review the pathophysiology of lipoprotein metabolism in selected rheumatologic disorders. The Adult Treatment Panel II of the National Cholesterol Education Program (NCEP) updated its guidelines for management of hypercholesterolemia in 1993. 13 A summary of these guidelines is shown in Table 1. The focus of these guidelines is on reduction of the LDL cholesterol level. The intensity with which LDL cholesterol is treated depends on the presence of existing ASCVD and, if absent, the presence and number of other cardiovascular risk factors. Traditional risk factors include age greater than 45 for men or greater than 55 for women, current cigarette smoking, hypertension, diabetes mellitus, a family history of premature ASCVD, or an HDL cholesterol level less than 35 mg/dL. An HDL cholesterol level greater than 60 mg/dL is considered protective against atherosclerosis and can be used to offset the effect of one risk factor. Patients with established ASCVD or two or more risk factors are treated most aggressively, including frequent use of drug therapy, whereas low-risk patients are generally managed with nonpharmacologic measures. This article also reviews the nonpharmacologic and pharmacologic approaches to reduction of LDL cholesterol in patients with rheumatologic disorders. Although the NCEP guidelines and current clinical practice are focused primarily on reducing LDL cholesterol, there is growing interest in the role of other lipoprotein-related cardiovascular risk factors. These include HDL, 14 triglycerides, 20 small dense LDL, 4 and lipoprotein(a) [Lp(a)]. 41 Evidence strongly suggests that each of these are independently associated with cardiovascular risk, although little clinical trial data exist demonstrating reduction in risk with therapy specifically directed against these risk factors. A third focus of this article is to review, when known, abnormalities of these additional lipid-related risk factors in rheumatologic conditions.

SummaryStickler and Marshall syndromes are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural-hearing deficit. Since the characteristics of these syndromes overlap, it has been argued whether they are distinct entities or different manifestations of a single syndrome. Several mutations causing Stickler syndrome have been found in the COL2A1 gene, and one mutation causing Stickler syndrome and one causing Marshall syndrome have been detected in the COL11A1 gene. We characterize here the genomic structure of the COL11A1 gene. Screening of patients with Stickler, Stickler-like, or Marshall syndrome pointed to 23 novel mutations. Genotypic-phenotypic comparison revealed an association between the Marshall syndrome phenotype and splicing mutations of 54-bp exons in the C-terminal region of the COL11A1 gene. Null-allele mutations in the COL2A1 gene led to a typical phenotype of Stickler syndrome. Some patients, however, presented with phenotypes of both Marshall and Stickler syndromes.

Paragangliomas are rare tumors and seldom cause endocrine hypertension. Germline mutations in the succinate dehydrogenase subunit B gene (SDHB) have been associated with malignant paragangliomas. We report a family with nonclassic congenital adrenal hyperplasia (CAH) in whom one member suffered from metastatic paraganglioma. A 13-year-old boy presented with delayed puberty, nocturnal enuresis, and headaches. His laboratory test results, including thyroid and adrenal tests, were within normal limits. MRI of the brain showed a lesion in the diploic space in the frontal region. CT of his head revealed a lytic bone lesion considered to likely be a histiocytic eosinophilic granuloma. A bone scan showed another lytic lesion in the right proximal femur. Bone biopsy of the skull lesion identified a paraganglioma, likely metastatic. Further imaging showed a 8 × 3 × 3 cm mass close to the vena cava and aorta. Blood pressure of this patient was normal; 24-hour urinary norepinephrine was slightly elevated, and he received preoperative therapy. After surgical tumor removal, postoperative MIBG showed persistent uptake in the abdomen and right femur. His sister was diagnosed to have 3-β-dehydrogenase deficiency; his grandmother had a pituitary adenoma. Germline mutation analysis of the SDHB gene, located at 1p36.13, revealed a known missense mutation (C.418G>T) and a previously unreported splice donor region DNA sequence variation in intron 2 (C.200+7A>G) in the index patient. His sister and father were heterozygous for this splice donor variation, whereas his mother was heterozygous for the known missense mutation. Whole-body imaging of the sister with nonclassic CAH was within normal limits. This case illustrates that malignant paragangliomas can occur in children and are associated with germline sequence variants in the SDHB gene. Clinical presentation may mimic histiocytosis and may include delayed puberty. The combination of sequence variations in the SDHB gene in the same patient may trigger tumor growth of selected chromaffin cells.

This study demonstrates that cytoplasmic malate dehydrogenase (MDH-s) catalyzes the reduction of aromatic alpha-keto acids in the presence of NADH, that the enzyme which has been described in the literature as aromatic alpha-keto acid reductase (KAR; EC 1.1.1.96) is identical to MDH-s, and that the reduction of aromatic alpha-keto acids is due predominantly to a previously unrecognized secondary activity of MDH-s and the remainder is due to the previously recognized activity of lactate dehydrogenase (LDH) toward aromatic keto-acids. MDH-s and KAR have the same molecular weight, subunit structure, and tissue distribution. Starch gel electrophoresis followed by histochemical staining using either p-hydroxy-phenylpyruvic acid (HPPA) or malate as the substrate shows that KAR activity comigrates with MDH-s in all species studied except some marine species. Inhibition with malate, the end product of the MDH reaction, substantially reduces or totally eliminates KAR activity. Genetically determined electrophoretic variants of MDH-s seen in the fresh water bony fish of the genus Xiphophorus and the amphibian Rana pipiens exhibited identical variation for KAR, and the two traits cosegregated in the offspring from one R. pipiens heterozygote studied. Both enzymes comigrate with no electrophoretic variation among several inbred strains of mice. Antisera raised against purified chicken MDH-s totally inhibited both MDH-s and KAR activity in chicken liver homogenates. There is no evidence to suggest that any protein besides MDH-s and LDH catalyzes this reaction with the possible exception of the situation in Xiphophorus, in which a third independent zone of HPPA reduction is observed. In most species the activity formerly described as KAR appears to be due to a previously unsuspected activity of MDH-s toward aromatic monocarboxylic alpha-keto acids. In all species examined the KAR activity is associated only with MDH-s; in tissue homogenates the mitochondrial form of MDH (MDH-m) is not detected after electrophoresis using HPPA as a substrate.

Summary We have recently shown that cytoplasmic malate dehydrogenase (MDH-s) from several non-human species catalyses the reduction of aromatic alpha-keto acids in the presence of NADH (Friedrich et al. 1987), an activity previously attributed to the enzyme aromatic alpha-keto acid reductase (KAR E.C. 1.1.1. 96). Here we present evidence that this also occurs in humans, and that the previously characterized human KAR is not the product of a genetically distinct locus. Human MDH-s and KAR activities co-migrate after starch gel electrophoresis, and electrophoretic variants of human MDH-s exhibited identical variation for KAR. Both enzymes show almost no electrophoretic variation among human populations of diverse origin. The reduction of aromatic alpha-keto acids is substantially inhibited by malate, the end-product of the MDH reaction. Antibodies raised against purified chicken MDH-s equally inhibited both MDH-s and KAR in chickens and humans. The bulk of the KAR activity in human blood appears to be due to MDH-s, with a minor fraction catalysed by LDH, as is the case in most other species studied. The previous assignment of a gene for KAR to human chromosome 12 in human/Chinese hamster somatic cell hybrids is questioned because interspecific hybrid bands of both MDH-s and LDH appear with slightly different mobility approximately midway between the human and hamster controls in somatic cell hybrid studies, and the meaning of this artifact is discussed. The discovery that MDH reacts with intermediate metabolites of phenylalanine and tyrosine has implications in relation to the mechanism by which mental retardation may be produced in phenylketonuria (PKU), and the effect of MDH inhibition on oxidative phosphorylation in the various tyrosinaemias is discussed.